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Guha Ray A, Odum OP, Wiseman D, Weinstock A. The diverse roles of macrophages in metabolic inflammation and its resolution. Front Cell Dev Biol 2023; 11:1147434. [PMID: 36994095 PMCID: PMC10041730 DOI: 10.3389/fcell.2023.1147434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Macrophages are one of the most functionally diverse immune cells, indispensable to maintain tissue integrity and metabolic health. Macrophages perform a myriad of functions ranging from promoting inflammation, through inflammation resolution to restoring and maintaining tissue homeostasis. Metabolic diseases encompass a growing list of diseases which develop from a mix of genetics and environmental cues leading to metabolic dysregulation and subsequent inflammation. In this review, we summarize the contributions of macrophages to four metabolic conditions-insulin resistance and adipose tissue inflammation, atherosclerosis, non-alcoholic fatty liver disease and neurodegeneration. The role of macrophages is complex, yet they hold great promise as potential therapies to address these growing health concerns.
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Affiliation(s)
| | | | | | - Ada Weinstock
- Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, United States
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2
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Shao L, Chen Y, Li J, Chao J, Yang Z, Ding Y, Shen H, Chen Y, Shen Z. Hypoxia-Elicited Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Alleviate Myocardial Infarction by Promoting Angiogenesis through the miR-214/Sufu Pathway. Stem Cells Int 2023; 2023:1662182. [PMID: 39280589 PMCID: PMC11401710 DOI: 10.1155/2023/1662182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 12/15/2022] [Accepted: 12/24/2022] [Indexed: 09/18/2024] Open
Abstract
Objective Myocardial infarction is a leading cause of mortality worldwide. Angiogenesis in the infarct border zone is vital for heart function restoration after myocardial infarction. Hypoxia-induced MSC modification is a safe and effective approach for angiogenesis in clinical therapy; however, the mechanism still requires further investigation. In our study, we preconditioned human umbilical cord mesenchymal stem cells (huMSCs) with hypoxia and isolated the small extracellular vesicles (sEVs) to promote cardiac repair. We also investigated the potential mechanisms. Method huMSCs were preconditioned with hypoxia (1% O2 and 5% CO2 at 37°C for 48 hours), and their sEVs were isolated using the Total Exosome Isolation reagent kit. To explore the role of miR-214 in MSC-derived sEVs, sEVs with low miR-214 expression were prepared by transfecting miR-214 inhibitor into huMSCs before hypoxia pretreatment. Scratch assays and tube formation assays were performed in sEVs cocultured with HUVECs to assess the proangiogenic capability of MSC-sEVs and MSChyp-sEVs. Rat myocardial infarction models were used to investigate the ability of miR-214-differentially expressed sEVs in cardiac repair. Echocardiography, Masson's staining, and immunohistochemical staining for CD31 were performed to assess cardiac function, the ratio of myocardial fibrosis, and the capillary density after sEV implantation. The potential mechanism by which MSChyp-sEVs enhance angiogenesis was explored in vitro by RT-qPCR and western blotting. Results Tube formation and scratch assays demonstrated that the proangiogenic capability of huMSC-derived sEVs was enhanced by hypoxia pretreatment. Echocardiography and Masson's staining showed greater improvements in heart function and less ventricular remodeling after MSChyp-sEV transplantation. The angiogenic capability was reduced following miR-214 knockdown in MSChyp-sEVs. Furthermore, Sufu, a target of miR-214, was decreased, and hedgehog signaling was activated in HUVECs. Conclusion We found that hypoxia induced miR-214 expression both in huMSCs and their sEVs. Transplantation of MSChyp-sEVs into a myocardial infarction model improved cardiac repair by increasing angiogenesis. Mechanistically, MSChyp-sEVs promote HUVEC tube formation and migration by transferring miR-214 into recipient cells, inhibiting Sufu expression, and activating the hedgehog pathway. Hypoxia-induced vesicle modification is a feasible way to restore heart function after myocardial infarction.
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Affiliation(s)
- Lianbo Shao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Jingjing Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Jingfan Chao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Ziying Yang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Yinglong Ding
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Han Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Yueqiu Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China
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3
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Ding J, Li H, Liu W, Wang X, Feng Y, Guan H, Chen Z. miR-186-5p Dysregulation in Serum Exosomes from Patients with AMI Aggravates Atherosclerosis via Targeting LOX-1. Int J Nanomedicine 2022; 17:6301-6316. [PMID: 36536941 PMCID: PMC9758944 DOI: 10.2147/ijn.s383904] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
Purpose The formation of macrophage-derived foam cells via the uptake of modified lipoproteins is a pivotal development event in atherosclerosis. It has been reported that clinical and experimental myocardial infarction could accelerate atherosclerosis. Several studies have suggested the critical role of exosomes in cardiovascular diseases. However, the role of exosomes from patients with acute myocardial infarction (AMI) patients in atherogenesis remains unclear. Patients and Methods Serum exosomes from AMI patients (AMI-Exo) and control individuals (Con-Exo) were isolated and characterized. These exosomes were studied in vitro and in vivo to determine their impact on macrophage foaming and atherogenesis. Results Our results showed that AMI-Exo promoted foam cell formation in oxidized low-density lipoprotein (ox-LDL)-treated macrophages and progression of atherosclerosis in high-fat/cholesterol diet-fed ApoE-/- mice together with a significantly upregulated levels of lectin-like ox-LDL receptor-1 (LOX-1). The miR-186-5p was found to be downregulated in AMI-Exo and macrophages administered with AMI-Exo. Moreover, serum exosomal miR-186-5p achieved high diagnostic performance for AMI. Luciferase reporter assay indicated that miR-186-5p directly inhibited LOX-1. The endogenous or exogenous miR-186-5p deficiency enhanced lipid accumulation by upregulating LOX-1, whereas miR-186-5p mimics had a reverse effect. Conclusion In conclusion, the current findings suggest that dysregulated miR-186-5p in AMI-Exo may explain the contribution of acute ischemia events to the advancement of atherosclerosis by enhancing macrophage foaming via its target, LOX-1.
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Affiliation(s)
- Jiaxing Ding
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China,Department of Cardiology, Henan Provincial Key Lab for Control of Coronary Heart Disease, Henan Provincial People’s Hospital Heart Center, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China
| | - Huili Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Wei Liu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Xuehua Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yu Feng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Hongquan Guan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China,Correspondence: Zhijian Chen; Hongquan Guan, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Tel + 86 27 85726011, Fax +86 27 85727340, Email
| | - Zhijian Chen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
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4
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Kabłak-Ziembicka A, Badacz R, Przewłocki T. Clinical Application of Serum microRNAs in Atherosclerotic Coronary Artery Disease. J Clin Med 2022; 11:6849. [PMID: 36431326 PMCID: PMC9698927 DOI: 10.3390/jcm11226849] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
MicroRNAs (miRs) are promising diagnostic, prognostic and therapeutic biomolecules for atherosclerotic cardiovascular disease. Atherosclerotic occlusive disease concerns a large population of patients, carrying the highest incidence of fatal and non-fatal adverse events, such as myocardial infarction, ischemic stroke, and limb ischemia, worldwide. Consistently, miRs are involved in regulation and pathogenesis of atherosclerotic coronary artery disease (CAD), acute coronary syndromes (ACS), both with ST-segment (STEMI) and non-ST segment elevation myocardial infarctions (NSTEMI), as well as cardiac remodeling and fibrosis following ACS. However, the genetic and molecular mechanisms underlying adverse outcomes in CAD are multifactorial, and sometimes difficult to interpret for clinicians. Therefore, in the present review paper we have focused on the clinical meaning and the interpretation of various miRs findings, and their potential application in routine clinical practice.
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Affiliation(s)
- Anna Kabłak-Ziembicka
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, św. Anny 12, 31-007 Kraków, Poland
- Noninvasive Cardiovascular Laboratory, The John Paul II Hospital, Prądnicka 80, 31-202 Kraków, Poland
| | - Rafał Badacz
- Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University Medical College, św. Anny 12, 31-007 Kraków, Poland
- Department of Interventional Cardiology, The John Paul II Hospital, Prądnicka 80, 31-202 Kraków, Poland
| | - Tadeusz Przewłocki
- Department of Interventional Cardiology, The John Paul II Hospital, Prądnicka 80, 31-202 Kraków, Poland
- Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, św. Anny 12, 31-007 Kraków, Poland
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5
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Jin Y, Lu J, Liu F, Yang X, Chen F, Zhang J. MiR-4291 stabilized the vulnerable atherosclerotic plaques by degrading the MAPK1/ERK2 in ApoE -/- mice. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1243. [PMID: 36544668 PMCID: PMC9761127 DOI: 10.21037/atm-22-5241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022]
Abstract
Background This study sought to explore the mechanism of action of the micro ribonucleic acid (miR)-4291 in stabilizing atherosclerotic (AS) plaques. Methods An AS model of apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (HFD) was established. Oxidized low-density lipoprotein (ox-LDL) was used to induce an inflammatory response of RAW264.7 macrophages. The mice were divided into the normal diet (ND) + miR-4291 negative control (NC) group, the ND + miR-4291 mimic group, the HFD + miR-4291 NC group, and the HFD + miR-4291 mimic group. They were also classified into the miR-4291 NC group, the miR-4291 mimic group, the ox-LDL + miR-4291 NC group, and the ox-LDL + miR-4291 mimic group. The arterial plaque burden of the mice was assessed by hematoxylin-eosin staining and immunohistochemistry, and the expression of phosphorylated-extracellular signal-regulated kinase 2 (p-ERK2) and related proteins in the arterial plaques and RAW264.7 macrophages of the mice were detected by Western blotting. Results Obvious plaques with massive macrophage infiltration were found in the aortic roots of the mice fed a HFD, and smooth muscle cells were found at the margin of the plaques. In the HFD + miR-4291 mimic group, the number of plaques and macrophages was significantly declined, but there were no significant changes in the smooth muscle cells compared to those in the HFD + miR-4291 NC group. The Western blot results showed that miR-4291 reduced the protein expression of p-ERK1-2, t-ERK1-2, TNF-α, MCP-1, MMP-1, MMP-3, and MMP-9 in the AS plaques and the ox-LDL-induced RAW264.7 macrophages of the mice fed a HFD. Conclusions MiR-4291 reduced the expression of MMP-2/9 by inhibiting the activity of ERK2, which in turn increased the fibrous cap thickness and stabilized the vulnerable plaques in AS.
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Ishiguro T, Hayashi M, Fujiwara W, Okumura S, Yoshinaga M, Yamada R, Ueda S, Ito T, Niwa Y, Miyazaki A, Harada M, Naruse H, Ishii J, Ozaki Y, Izawa H. Circulating miR-489 as a potential new biomarker for idiopathic dilated cardiomyopathy. FUJITA MEDICAL JOURNAL 2022; 7:18-22. [PMID: 35111539 PMCID: PMC8749486 DOI: 10.20407/fmj.2020-001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/20/2020] [Indexed: 01/15/2023]
Abstract
Objectives:
MicroRNAs (miRNA) are functional RNAs that have emerged as pivotal gene expression
regulators in cardiac disease. Although several cardiomyocyte miRNAs have been reported to
play roles in heart failure progression among patients with idiopathic dilated cardiomyopathy
(DCM), the role of circulating miRNAs has not yet been well-examined. Methods:
After total RNA extraction from the peripheral blood samples of three control
participants and six patients with DCM, miRNA profiling was performed using miRNA arrays.
Based on the results of this initial screening, real-time polymerase chain reaction (RT-PCR)
was used to perform a quantitative analysis of blood samples from a larger number of matched
patients (DCM, n=20; controls, n=5). Finally, the
correlations between specific miRNA expression levels and hemodynamic parameters were
analyzed. Results:
A primary screening of 2,565 miRNAs resulted in the identification of nine miRNA
candidates. Quantitative RT-PCR results revealed significantly increased miR-489 expression
levels in the DCM group. Moreover, there was a significant positive correlation between
miR-489 expression level and left ventricular ejection fraction. Conclusions:
Our results suggest that circulating miR-489 could be a potential noninvasive
diagnostic biomarker for DCM. Additionally, the quantification of circulating miR-489 may have
value as a potential prognostic marker for patients with DCM.
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Affiliation(s)
- Tomoya Ishiguro
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Mutsuharu Hayashi
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Wakaya Fujiwara
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Satoshi Okumura
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Masataka Yoshinaga
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Ryo Yamada
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Sayano Ueda
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Takehiro Ito
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Yudai Niwa
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Akane Miyazaki
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
| | - Masahide Harada
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Hiroyuki Naruse
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Junnichi Ishii
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Yukio Ozaki
- Department of Cardiology, Fujita Health University, School of Medicine, Toyoake, Aichi, Japan
| | - Hideo Izawa
- Department of Cardiology, Fujita Health University Bantane Hospital, Nagoya, Aichi, Japan
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MicroRNA-214 in Health and Disease. Cells 2021; 10:cells10123274. [PMID: 34943783 PMCID: PMC8699121 DOI: 10.3390/cells10123274] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/16/2021] [Accepted: 11/20/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenously expressed, non-coding RNA molecules that mediate the post-transcriptional repression and degradation of mRNAs by targeting their 3′ untranslated region (3′-UTR). Thousands of miRNAs have been identified since their first discovery in 1993, and miR-214 was first reported to promote apoptosis in HeLa cells. Presently, miR-214 is implicated in an extensive range of conditions such as cardiovascular diseases, cancers, bone formation and cell differentiation. MiR-214 has shown pleiotropic roles in contributing to the progression of diseases such as gastric and lung cancers but may also confer cardioprotection against excessive fibrosis and oxidative damage. These contrasting functions are achieved through the diverse cast of miR-214 targets. Through silencing or overexpressing miR-214, the detrimental effects can be attenuated, and the beneficial effects promoted in order to improve health outcomes. Therefore, discovering novel miR-214 targets and understanding how miR-214 is dysregulated in human diseases may eventually lead to miRNA-based therapies. MiR-214 has also shown promise as a diagnostic biomarker in identifying breast cancer and coronary artery disease. This review provides an up-to-date discussion of miR-214 literature by describing relevant roles in health and disease, areas of disagreement, and the future direction of the field.
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8
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Sahoo S, Adamiak M, Mathiyalagan P, Kenneweg F, Kafert-Kasting S, Thum T. Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases: Roadmap to the Clinic. Circulation 2021; 143:1426-1449. [PMID: 33819075 PMCID: PMC8021236 DOI: 10.1161/circulationaha.120.049254] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Exosomes are small membrane-bound vesicles of endocytic origin that are actively secreted. The potential of exosomes as effective communicators of biological signaling in myocardial function has previously been investigated, and a recent explosion in exosome research not only underscores their significance in cardiac physiology and pathology, but also draws attention to methodological limitations of studying these extracellular vesicles. In this review, we discuss recent advances and challenges in exosome research with an emphasis on scientific innovations in isolation, identification, and characterization methodologies, and we provide a comprehensive summary of web-based resources available in the field. Importantly, we focus on the biology and function of exosomes, highlighting their fundamental role in cardiovascular pathophysiology to further support potential applications of exosomes as biomarkers and therapeutics for cardiovascular diseases.
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Affiliation(s)
- Susmita Sahoo
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York (S.S., M.A., P.M.)
| | - Marta Adamiak
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York (S.S., M.A., P.M.)
| | - Prabhu Mathiyalagan
- Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York (S.S., M.A., P.M.)
| | - Franziska Kenneweg
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (F.K., S.K-K., T.T.), Hannover Medical School, Germany
| | - Sabine Kafert-Kasting
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (F.K., S.K-K., T.T.), Hannover Medical School, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (S.K-K., T.T.)
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (F.K., S.K-K., T.T.), Hannover Medical School, Germany
- REBIRTH Center for Translational Regenerative Medicine (T.T.), Hannover Medical School, Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (S.K-K., T.T.)
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Shirazi-Tehrani E, Firouzabadi N, Tamaddon G, Bahramali E, Vafadar A. Carvedilol Alters Circulating MiR-1 and MiR-214 in Heart Failure. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2020; 13:375-383. [PMID: 32943906 PMCID: PMC7481348 DOI: 10.2147/pgpm.s263740] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/11/2020] [Indexed: 02/01/2023]
Abstract
Introduction MicroRNAs (miRNAs) are recognized as major contributors in various cardiovascular diseases, such as heart failure (HF). These small noncoding RNAs that posttranscriptionally control target genes are involved in regulating different pathophysiological processes including cardiac proliferation, ifferentiation, hypertrophy, and fibrosis. Although carvedilol, a β-adrenergic blocker, and a drug of choice in HF produce cytoprotective actions against cardiomyocyte hypertrophy, the mechanisms are poorly understood. Here we proposed that the expression of hypertrophic-specific miRNAs (miR-1, miR-133, miR-208, and miR-214) might be linked to beneficial effects of carvedilol. Methods The levels of four hypertrophic-specific miRNAs were measured in the sera of 35 patients with systolic HF receiving carvedilol (treated) and 20 HF patients not receiving any β-blockers (untreated) as well as 17 nonHF individuals (healthy) using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Systolic HF was defined as left ventricular ejection fraction <50% by transthoracic echocardiography. Results We demonstrated that miR-1 and miR-214 were significantly upregulated in the treated group compared to the untreated group (P=0.014 and 5.3-fold, 0.033 and 4.2-fold, respectively). However, miR-133 and miR-208 did not show significant difference in expression between these two study groups. MiR-1 was significantly downregulated in the untreated group compared with healthy individuals (P=0.019 and 0.14-fold). Conclusion In conclusion, it might be postulated that one of the mechanisms by which carvedilol may exert its cardioprotective effects can be through increasing miR-1 and miR-214 expressions which may also serve as a potential therapeutic target in patients with systolic HF in future.
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Affiliation(s)
- Elham Shirazi-Tehrani
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.,Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Gholamhossein Tamaddon
- Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Bahramali
- Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Asma Vafadar
- Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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10
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Zhai C, Li R, Hou K, Chen J, Alzogool M, Hu Y, Zhang J, Zhang Y, Wang L, Zhang R, Cong H. Value of Blood-Based microRNAs in the Diagnosis of Acute Myocardial Infarction: A Systematic Review and Meta-Analysis. Front Physiol 2020; 11:691. [PMID: 32922300 PMCID: PMC7456928 DOI: 10.3389/fphys.2020.00691] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/27/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Recent studies have shown that blood-based miRNAs are dysregulated in patients with acute myocardial infarction (AMI) and are therefore a potential tool for the diagnosis of AMI. Therefore, this study summarized and evaluated studies focused on microRNAs as novel biomarkers for the diagnosis of AMI from the last ten years. Methods: MEDLINE, the Cochrane Central database, and EMBASE were searched between January 2010 and December 2019. Studies that assessed the diagnostic accuracy of circulating microRNAs in AMI were chosen. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve (AUC) were used to assess the test performance of miRNAs. Results: A total of 58 studies that included 8,206 participants assessed the diagnostic accuracy of circulating miRNAs in AMI. The main results of the meta-analyses are as follows: (1) Total miRNAs: the overall pooled sensitivity and specificity were 0.82 (95% CI: 0.79-0.85) and 0.87 (95% CI: 0.84-0.90), respectively. The AUC value was 0.91 (95% CI: 0.88-0.93) in the overall summary receiver operator characteristic (SROC) curve. (2) The panel of two miRNAs: sensitivity: 0.88 (95% CI: 0.77-0.94), specificity: 0.84 (95% CI: 0.72-0.91), AUC: 0.92 (95% CI: 0.90-0.94). (3) The panel of three miRNAs: sensitivity: 0.91 (95% CI: 0.85-0.94), specificity: 0.87 (95% CI: 0.77-0.92), AUC: 0.92 (95% CI: 0.89-0.94). (4) Results by types of miRNAs: miRNA-1: sensitivity: 0.78 (95% CI: 0.71-0.84), specificity: 0.86 (95% CI: 0.77-0.91), AUC: 0.88 (95% CI: 0.85-0.90); miRNA-133a: sensitivity: 0.85 (95% CI: 0.69-0.94), specificity: 0.92 (95% CI: 0.61-0.99), AUC: 0.93 (95% CI: 0.91-0.95); miRNA-208b: sensitivity: 0.80 (95% CI: 0.69-0.88), specificity: 0.96 (95% CI: 0.77-0.99), AUC: 0.91 (95% CI: 0.88-0.93); miRNA-499: sensitivity: 0.85 (95% CI: 0.77-0.91), specificity: 0.95 (95% CI: 0.89-0.98), AUC: 0.96 (95% CI: 0.94-0.97). Conclusion: miRNAs may be used as potential biomarkers for the detection of AMI. For single, stand-alone miRNAs, miRNA-499 may have better diagnostic accuracy compared to other miRNAs. We propose that a panel of multiple miRNAs with high sensitivity and specificity should be tested.
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Affiliation(s)
- ChuanNan Zhai
- School of Medicine, NanKai University, Tianjin, China.,Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - Rui Li
- Tianjin GongAn Hospital, Tianjin, China
| | - Kai Hou
- School of Medicine, NanKai University, Tianjin, China.,Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - JingYi Chen
- School of Medicine, NanKai University, Tianjin, China
| | | | - YueCheng Hu
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - JingXia Zhang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - YingYi Zhang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - Le Wang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - Rui Zhang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
| | - HongLiang Cong
- School of Medicine, NanKai University, Tianjin, China.,Department of Cardiology, Tianjin Chest Hospital, Tianjin, China
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Samidurai A, Xi L, Salloum FN, Das A, Kukreja RC. PDE5 inhibitor sildenafil attenuates cardiac microRNA 214 upregulation and pro-apoptotic signaling after chronic alcohol ingestion in mice. Mol Cell Biochem 2020; 471:189-201. [PMID: 32535704 PMCID: PMC10801845 DOI: 10.1007/s11010-020-03779-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/03/2020] [Indexed: 12/17/2022]
Abstract
Abusive chronic alcohol consumption can cause metabolic and functional derangements in the heart and is a risk factor for development of non-ischemic cardiomyopathy. microRNA 214 (miR-214) is a molecular sensor of stress signals that negatively impacts cell survival. Considering cardioprotective and microRNA modulatory effects of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, we investigated the impact of chronic alcohol consumption on cardiac expression of miR-214 and its anti-apoptotic protein target, Bcl-2 and whether sildenafil attenuates such changes. Adult male FVB mice received unlimited access to either normal liquid diet (control), alcohol diet (35% daily calories intake), or alcohol + sildenafil (1 mg/kg/day, p.o.) for 14 weeks (n = 6-7/group). The alcohol-fed groups with or without sildenafil had increased total diet consumption and lower body weight as compared with controls. Echocardiography-assessed left ventricular function was unaltered by 14-week alcohol intake. Alcohol-fed group had 2.6-fold increase in miR-214 and significant decrease in Bcl-2 expression, along with enhanced phosphorylation of ERK1/2 and cleavage of PARP (marker of apoptotic DNA damage) in the heart. Co-ingestion with sildenafil blunted the alcohol-induced increase in miR-214, ERK1/2 phosphorylation, and maintained Bcl-2 and decreased PARP cleavage levels. In conclusion, chronic alcohol consumption triggers miR-214-mediated pro-apoptotic signaling in the heart, which was prevented by co-treatment with sildenafil. Thus, PDE5 inhibition may serve as a novel protective strategy against cardiac apoptosis due to chronic alcohol abuse.
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Affiliation(s)
- Arun Samidurai
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA
| | - Lei Xi
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA
| | - Fadi N Salloum
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA
| | - Anindita Das
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA
| | - Rakesh C Kukreja
- Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA.
- Division of Cardiology, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA.
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12
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Yang Q, Li J, Zhang H, Zuo H, Zhang Q, Cheng J. Down-regulation of microRNA-429 alleviates myocardial injury of rats with coronary heart disease. Cell Cycle 2019; 18:2550-2565. [PMID: 31438762 PMCID: PMC6738912 DOI: 10.1080/15384101.2019.1652037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
In recent years, the impact of microRNAs (miRNAs) on coronary heart disease (CHD) has been identified. This study was aimed to investigate the regulative role of microRNA (miR-429) in myocardial injury of rats with CHD. Expression of miR-429 in CHD patients and healthy people was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The CHD rat models were injected with normal saline, mimics negative control (NC), miR-429 mimics, inhibitors NC and miR-429 inhibitors twice a week, for 4 weeks. Levels of inflammatory factors, oxidative stress indices as well as apoptosis of cardiomyocytes were determined by a series of assays. Expression of miR-429 was up-regulated in CHD patients. Reduced miR-429 could decline the expression of oxidative stress-related factors and inflammation-related factors, and inhibit the apoptosis of cardiomyocytes in rats with CHD. Moreover, the down-regulation of miR-429 could promote the expression of CrkL and repress activation of the MEK/ERK signaling pathway. This study reveals that restrained miR-429 could exert a protective impact on myocardial injury of rats with CHD by suppressing oxidative stress, inflammation reaction and apoptosis of cardiomyocytes. The function mechanisms may relate to the up-regulation of CrkL and inhibition of the MEK/ERK signaling pathway.
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Affiliation(s)
- Qin Yang
- Emergency Department, Attending doctor, The Second Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
| | - Jingrong Li
- Emergency Department, The second Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
| | - Hao Zhang
- Emergency Department, The second Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
| | - Heping Zuo
- Emergency Department, The second Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
| | - Qinglong Zhang
- Emergency Department, The second Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
| | - Jinglin Cheng
- Emergency Department, Chief physician, The second Affiliated Hospital of Anhui Medical University , Hefei , Anhui , China
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13
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Melak T, Baynes HW. Circulating microRNAs as possible biomarkers for coronary artery disease: a narrative review. EJIFCC 2019; 30:179-194. [PMID: 31263392 PMCID: PMC6599194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Coronary artery disease is one of the most common cardiovascular diseases in the world. Involvement of microRNAs on the pathogenesis of this disease was reported either in beneficial or detrimental way. Different studies have also speculated that circulating microRNAs can be applied as promising biomarkers for the diagnosis of coronary artery disease. Particularly, microRNA-133a seems to fulfill the criteria of ideal biomarkers due to its role in the diagnosis, severity assessment and in prognosis. The panel of circulating microRNAs has also improved the predictive power of coronary artery disease compared to single microRNAs. In this review, the role of circulating microRNAs for early detection, severity assessment and prognosis of coronary artery disease were reviewed.
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Affiliation(s)
- Tadele Melak
- Department of Clinical Chemistry, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Northwest Ethiopia, Ethiopia
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14
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Chang TY, Tsai WC, Huang TS, Su SH, Chang CY, Ma HY, Wu CH, Yang CY, Lin CH, Huang PH, Cheng CC, Cheng SM, Wang HW. Dysregulation of endothelial colony-forming cell function by a negative feedback loop of circulating miR-146a and -146b in cardiovascular disease patients. PLoS One 2017; 12:e0181562. [PMID: 28727754 PMCID: PMC5519171 DOI: 10.1371/journal.pone.0181562] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 07/03/2017] [Indexed: 11/19/2022] Open
Abstract
Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease (CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients’ body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson’s correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3’-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases.
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Affiliation(s)
- Ting-Yu Chang
- Research Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chi Tsai
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Tse-Shun Huang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
- Institute of Engineering in Medicine, University of California, San Diego, United States of America
| | - Shu-Han Su
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Chih-Young Chang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Hsiu-Yen Ma
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Hsien Wu
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Chih-Yung Yang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Chi-Hung Lin
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Po-Hsun Huang
- Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, Taipei, Taiwan
| | - Cheng-Chung Cheng
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shu-Meng Cheng
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- * E-mail:
| | - Hsei-Wei Wang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
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15
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Infante T, Forte E, Schiano C, Cavaliere C, Tedeschi C, Soricelli A, Salvatore M, Napoli C. An integrated approach to coronary heart disease diagnosis and clinical management. Am J Transl Res 2017; 9:3148-3166. [PMID: 28804537 PMCID: PMC5553869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 06/16/2017] [Indexed: 06/07/2023]
Abstract
The major issue in coronary heart disease (CHD) diagnosis and management is that symptoms onset in an advanced state of disease. Despite the availability of several clinical risk scores, the prediction of cardiovascular events is lacking, and many patients at risk are not well stratified according to the canonical risk factors alone. Therefore, adequate risk assessment remains the most challenging issue. Recently, the integration of imaging data with biochemical markers in a radiogenomic framework has been proposed in many fields of medicine as well as in cardiology. Multimodal imaging and advanced processing techniques can provide both direct (e.g., remodeling index, calcium score, total plaque volume, plaque burden) and indirect (e.g., myocardial perfusion index, coronary flow reserve) imaging features of CHD. Furthermore, the identification of novel non-invasive biochemical markers, mainly focused on plasma and/or serum samples, has increased the specificity of findings, reflecting several pathophysiological pathways of atherosclerosis, the principal actor in CHD. In this context, a multifaced approach, derived from the strengths of all these modalities, appears promising for finer risk stratification and treatment strategies, facilitating the decision-making and clinical management of patients. This review underlines the role of different imaging modalities in the quantification of coronary atherosclerosis and describes novel blood-based markers that could improve diagnosis and have a better predictive value in CHD.
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Affiliation(s)
| | | | | | | | - Carlo Tedeschi
- Department of Cardiology, San Giovanni Bosco HospitalASL Napoli 1, Naples, Italy
| | - Andrea Soricelli
- IRCCS SDNNaples, Italy
- Department of Motor Sciences and Healthiness, University of Naples ParthenopeNaples, Italy
| | | | - Claudio Napoli
- IRCCS SDNNaples, Italy
- U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Department of Internal and Specialty Medicine Azienda Universitaria Policlinico (AOU), Università degli Studi della Campania “Luigi Vanvitelli”Naples, Italy
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16
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Circulating microRNA-214 and -126 as potential biomarkers for canine neoplastic disease. Sci Rep 2017; 7:2301. [PMID: 28536479 PMCID: PMC5442106 DOI: 10.1038/s41598-017-02607-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/13/2017] [Indexed: 01/08/2023] Open
Abstract
Circulating microRNAs in the blood may provide diagnostic and prognostic information about canine neoplastic diseases, and their profiles may be conserved between human and canine species. We performed RT-qPCR to obtain the profiles of circulating plasma microRNA-214 and -126 in total 181 cases of canine neoplastic diseases and healthy controls. MicroRNA-214 levels were high in 2 epithelial tumours (thyroid and mammary carcinomas) and 4 non-epithelial tumours (osteosarcoma, histiocytic sarcoma, chondrosarcoma, and hemangiosarcoma). In contrast, microRNA-126 levels were high in 6 epithelial tumours (mammary, hepatocellular, squamous cell, thyroid, transitional cell carcinomas, and adenocarcinoma) and 4 non-epithelial tumours (osteosarcoma, mast cell tumour, melanoma, and hemangiosarcoma). The diagnostic potential of microRNA-214 was relatively high in sarcomas, whereas that of microR-126 was high in most types of the tumours. MicroRNA-214 and -126 were prognostic predictors in 2 groups (adenocarcinoma and non-epithelial tumours except for osteosarcoma) and 3 groups (epithelial tumours, adenocarcinoma, and melanoma), respectively. Additionally, the microRNA levels did not show a strong correlation with the other clinical parameters. In conclusion, circulating microRNA-214 and -126 have the potential to be diagnostic and prognostic biomarkers for canine neoplastic diseases. Furthermore, their profiles may be key references as well for exploring novel biomarkers for human cancers.
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17
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Gabunia K, Herman AB, Ray M, Kelemen SE, England RN, DeLa Cadena R, Foster WJ, Elliott KJ, Eguchi S, Autieri MV. Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. J Mol Cell Cardiol 2017; 105:38-48. [PMID: 28257760 DOI: 10.1016/j.yjmcc.2017.02.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/21/2017] [Accepted: 02/27/2017] [Indexed: 10/20/2022]
Abstract
The transformation of vascular smooth muscle cells [VSMC] into foam cells leading to increased plaque size and decreased stability is a key, yet understudied step in atherogenesis. We reported that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine, attenuates atherosclerosis by anti-inflammatory effects on VSMC. In this work we report that IL-19 induces expression of miR133a, a muscle-specific miRNA, in VSMC. Although previously unreported, we report that miR133a can target and reduce mRNA abundance, mRNA stability, and protein expression of Low Density Lipoprotein Receptor Adaptor Protein 1, (LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the Autosomal Recessive Hypercholesterolemia (ARH) disorder in humans. Herein we show that IL-19 reduces lipid accumulation in VSMC, and LDLRAP1 expression and oxLDL uptake in a miR133a-dependent mechanism. We show that LDLRAP1 is expressed in plaque and neointimal VSMC of mouse and human injured arteries. Transfection of miR133a and LDLRAP1 siRNA into VSMC reduces their proliferation and uptake of oxLDL. miR133a is significantly increased in plasma from hyperlipidemic compared with normolipidemic patients. Expression of miR133a in IL-19 stimulated VSMC represents a previously unrecognized link between vascular lipid metabolism and inflammation, and may represent a therapeutic opportunity to combat vascular inflammatory diseases.
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Affiliation(s)
- Khatuna Gabunia
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Allison B Herman
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Mitali Ray
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Sheri E Kelemen
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Ross N England
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Raul DeLa Cadena
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - William J Foster
- Departments of Ophthalmology & Bioengineering, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Katherine J Elliott
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Satoru Eguchi
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States
| | - Michael V Autieri
- Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States.
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18
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Afzal TA, Luong LA, Chen D, Zhang C, Yang F, Chen Q, An W, Wilkes E, Yashiro K, Cutillas PR, Zhang L, Xiao Q. NCK Associated Protein 1 Modulated by miRNA-214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia. J Am Heart Assoc 2016; 5:e004629. [PMID: 27927633 PMCID: PMC5210428 DOI: 10.1161/jaha.116.004629] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 10/28/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND MicroRNA miR-214 has been implicated in many biological cellular functions, but the impact of miR-214 and its target genes on vascular smooth muscle cell (VSMC) proliferation, migration, and neointima smooth muscle cell hyperplasia is unknown. METHODS AND RESULTS Expression of miR-214 was closely regulated by different pathogenic stimuli in VSMCs through a transcriptional mechanism and decreased in response to vascular injury. Overexpression of miR-214 in serum-starved VSMCs significantly decreased VSMC proliferation and migration, whereas knockdown of miR-214 dramatically increased VSMC proliferation and migration. Gene and protein biochemical assays, including proteomic analyses, showed that NCK associated protein 1 (NCKAP1)-a major component of the WAVE complex that regulates lamellipodia formation and cell motility-was negatively regulated by miR-214 in VSMCs. Luciferase assays showed that miR-214 substantially repressed wild-type but not the miR-214 binding site mutated version of NCKAP1 3' untranslated region luciferase activity in VSMCs. This result confirmed that NCKAP1 is the functional target of miR-214 in VSMCs. NCKAP1 knockdown in VSMCs recapitulates the inhibitory effects of miR-214 overexpression on actin polymerization, cell migration, and proliferation. Data from cotransfection experiments also revealed that inhibition of NCKAP1 is required for miR-214-mediated lamellipodia formation, cell motility, and growth. Importantly, locally enforced expression of miR-214 in the injured vessels significantly reduced NCKAP1 expression levels, inhibited VSMC proliferation, and prevented neointima smooth muscle cell hyperplasia after injury. CONCLUSIONS We uncovered an important role of miR-214 and its target gene NCKAP1 in modulating VSMC functions and neointima hyperplasia. Our findings suggest that miR-214 represents a potential therapeutic target for vascular diseases.
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Affiliation(s)
- Tayyab Adeel Afzal
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Le Anh Luong
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Dan Chen
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng Zhang
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Feng Yang
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qishan Chen
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Weiwei An
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Edmund Wilkes
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Kenta Yashiro
- Translational Medicine & Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Pedro R Cutillas
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Li Zhang
- Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qingzhong Xiao
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
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19
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Navickas R, Gal D, Laucevičius A, Taparauskaitė A, Zdanytė M, Holvoet P. Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review. Cardiovasc Res 2016; 111:322-37. [PMID: 27357636 PMCID: PMC4996262 DOI: 10.1093/cvr/cvw174] [Citation(s) in RCA: 248] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 05/19/2016] [Indexed: 12/31/2022] Open
Abstract
The aim of the present study is to identify microRNAs (miRs) with high potential to be used as biomarkers in plasma and/or serum to clinically diagnose, or provide accurate prognosis for survival in, patients with atherosclerosis, coronary artery disease, and acute coronary syndrome (ACS). A systematic search of published original research yielded a total of 72 studies. After review of the risk of bias of the published studies, according to Cochrane Collaboration and the QUADUAS Group standards, 19 studies were selected. Overall 52 different miRs were reported. In particular, miR-133a/b (5 studies), miR-208a/b (6 studies), and miR-499 (7 studies) were well studied and found to be significant diagnostic and/or prognostic markers across different cardiovascular disease progression stages. miR-1 and miR-145b are potential biomarkers of ACS; miR-1 with higher sensitivity for all acute myocardial infarction (AMI), and miR-145 for STEMI and worse outcome of AMI. But when miRs were studied across different ACS study populations, patients had varying degrees of coronary stenosis, which was identified as an important confounder that limited the ability to quantitatively pool the study results. The identified miRs were found to regulate endothelial function and angiogenesis (miR-1, miR-133), vascular smooth muscle cell differentiation (miR-133, miR-145), communication between vascular smooth muscle and endothelial cell to stabilize plaques (miR-145), apoptosis (miR-1, miR-133, miR-499), cardiac myocyte differentiation (miR-1, miR-133, miR-145, miR-208, miR-499), and to repress cardiac hypertrophy (miR-133). Their role in these processes may be explained by regulation of shared RNA targets such as cyclin-dependent kinase inhibitor 1A (or p21), ETS proto-oncogene 1, fascin actin-bundling protein 1, hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, insulin-like growth factor 1 receptor LIM and SH3 protein 1, purine nucleoside phosphorylase, and transgelin 2. These mechanistic data further support the clinical relevance of the identified miRs. miR-1, miR-133a/b, miR-145, miR-208a/b, and miR-499(a) in plasma and/or serum show some potential for diagnosis of cardiovascular disease. However, biased selection of miRs in most studies and unexplained contrasting results are major limitations of current miR research. Inconsistencies need to be addressed in order to definitively identify clinically useful miRs. Therefore, this paper presents important aspects to improve future miR research, including unbiased selection of miRs, standardization/normalization of reference miRs, adjustment for patient comorbidities and medication, and robust protocols of data-sharing plans that could prevent selective publication and selective reporting of miR research outcomes.
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Affiliation(s)
- Rokas Navickas
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania
| | - Diane Gal
- Department of Cardiovascular Sciences, Atherosclerosis and Metabolism Unit, KU Leuven, Leuven, Belgium
| | - Aleksandras Laucevičius
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania Vilnius University Hospital Santariškių Klinikos, Vilnius, Lithuania
| | | | | | - Paul Holvoet
- Department of Cardiovascular Sciences, Atherosclerosis and Metabolism Unit, KU Leuven, Leuven, Belgium
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20
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Rathan S, Ankeny CJ, Arjunon S, Ferdous Z, Kumar S, Fernandez Esmerats J, Heath JM, Nerem RM, Yoganathan AP, Jo H. Identification of side- and shear-dependent microRNAs regulating porcine aortic valve pathogenesis. Sci Rep 2016; 6:25397. [PMID: 27151744 PMCID: PMC4858741 DOI: 10.1038/srep25397] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 04/05/2016] [Indexed: 02/06/2023] Open
Abstract
Aortic valve (AV) calcification is an inflammation driven process that occurs preferentially in the fibrosa. To explore the underlying mechanisms, we investigated if key microRNAs (miRNA) in the AV are differentially expressed due to disturbed blood flow (oscillatory shear (OS)) experienced by the fibrosa compared to the ventricularis. To identify the miRNAs involved, endothelial-enriched RNA was isolated from either side of healthy porcine AVs for microarray analysis. Validation using qPCR confirmed significantly higher expression of 7 miRNAs (miR-100, -130a, -181a/b, -199a-3p, -199a-5p, and -214) in the fibrosa versus the ventricularis. Upon bioinformatics analysis, miR-214 was selected for further investigation using porcine AV leaflets in an ex vivo shear system. Fibrosa and ventricularis sides were exposed to either oscillatory or unidirectional pulsatile shear for 2 days and 3 & 7 days in regular and osteogenic media, respectively. Higher expression of miR-214, increased thickness of the fibrosa, and calcification was observed when the fibrosa was exposed to OS compared to the ventricularis. Silencing of miR-214 by anti-miR-214 in whole AV leaflets with the fibrosa exposed to OS significantly increased the protein expression of TGFβ1 and moderately increased collagen content but did not affect AV calcification. Thus, miR-214 is identified as a side- and shear-dependent miRNA that regulates key mechanosensitive gene in AV such as TGFβ1.
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Affiliation(s)
- Swetha Rathan
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Casey J Ankeny
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Sivakkumar Arjunon
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Zannatul Ferdous
- Mechanical, Aerospace and Biomedical Engineering, University of Tennessee Knoxville, TN, USA
| | - Sandeep Kumar
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Joan Fernandez Esmerats
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Jack M Heath
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Robert M Nerem
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Ajit P Yoganathan
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.,The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Hanjoong Jo
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
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Napoli C, Grimaldi V, De Pascale MR, Sommese L, Infante T, Soricelli A. Novel epigenetic-based therapies useful in cardiovascular medicine. World J Cardiol 2016; 8:211-219. [PMID: 26981216 PMCID: PMC4766271 DOI: 10.4330/wjc.v8.i2.211] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/28/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Epigenetic modifications include DNA methylation, histone modifications, and microRNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of CpG islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression (e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of microRNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense microRNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of emerging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols.
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Ding XQ, Ge PC, Liu Z, Jia H, Chen X, An FH, Li LH, Chen ZH, Mao HW, Li ZY, Gu Y, Zhu TB, Li CJ, Wang LS, Ma WZ, Yang ZJ, Jia EZ. Interaction between microRNA expression and classical risk factors in the risk of coronary heart disease. Sci Rep 2015; 5:14925. [PMID: 26446730 PMCID: PMC4597355 DOI: 10.1038/srep14925] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 09/09/2015] [Indexed: 01/07/2023] Open
Abstract
The aim of this study was to identify the synergistic effect of microRNA expression with classical risk factors of coronary heart disease (CHD) and to explore their diagnostic value for coronary stenotic lesions in subjects with CHD. Plasma samples were obtained from 66 subjects with CHD and from 58 control individuals. A quantitative reverse-transcription PCR (RT-qPCR) assay was conducted to confirm the relative expressions of the known CHD-related miRNAs. The severity of coronary atherosclerosis was based on the Gensini scoring system. The expression of miR-125b in plasma of the CHD group was lower than that of the non-CHD group (0.14 ± 0.09 vs. 0.18 ± 0.10, p = 0.055), and the miR-125b levels significantly decreased following an increasing Gensini score (P = 0.037). Spearman correlation analyses indicated the Gensini score was negatively associated with miR-125b (r = −0.215, p = 0.017). Of all the miRNAs, miR-125b showed the lowest AUC (0.405; 95% CI: 0.305 ~ 0.506, p = 0.070). We found several synergistic effects between miR-125b and classical risk factors, such as age, sex, CR, FBG and HDL-C; the proportion of CHD attributable to the interaction of miR-125b and age was as high as 80%. Therefore, miR-125b was shown to play an important role in individual’s susceptibility to developing CHD.
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Affiliation(s)
- Xiao-Qing Ding
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Peng-Cheng Ge
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Zhe Liu
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Heng Jia
- Kangda school, Nanjing Medical University, Lianyungang 222000, Jiangsu Province, China
| | - Xi Chen
- Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210029, Jiangsu Province, China
| | - Feng-Hui An
- Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining 835000, Xinjiang, China
| | - Li-Hua Li
- Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining 835000, Xinjiang, China
| | - Zhao-Hong Chen
- Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining 835000, Xinjiang, China
| | - Hong-Wei Mao
- Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining 835000, Xinjiang, China
| | - Zhao-Yang Li
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Yan Gu
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Tie-Bing Zhu
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Chun-Jian Li
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Lian-Sheng Wang
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Wen-Zhu Ma
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Zhi-Jian Yang
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - En-Zhi Jia
- First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
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23
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Duan Q, Yang L, Gong W, Chaugai S, Wang F, Chen C, Wang P, Zou MH, Wang DW. MicroRNA-214 Is Upregulated in Heart Failure Patients and Suppresses XBP1-Mediated Endothelial Cells Angiogenesis. J Cell Physiol 2015; 230:1964-73. [PMID: 25656649 PMCID: PMC4911176 DOI: 10.1002/jcp.24942] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 01/23/2015] [Indexed: 01/18/2023]
Abstract
More and more miRNAs have been shown to regulate gene expression in the heart and dysregulation of their expression has been linked to cardiovascular diseases including the miR‐199a/214 cluster. However, the signature of circulating miR‐214 expression and its possible roles during the development of heart failure has been less well studied. In this study, we elucidated the biological and clinical significance of miR‐214 dysregulation in heart failure. Firstly, circulating miR‐214 was measured by quantitative PCR, and we found that miR‐214 was upregulated in the serum of chronic heart failure patients, as well as in hypertrophic and failing hearts of humans and mice. Adeno‐associated virus serotype 9 (AAV9)‐mediated miR‐214 silencing attenuates isoproterenol (ISO) infusion‐induced cardiac dysfunction and impairment of cardiac angiogenesis in mice. Mechanistically, miR‐214 overexpression reduces angiogenesis of HUVECs by targeting XBP1, an important transcription factor of unfolded protein response, and XBP1 silencing decreases HUVECs proliferation and angiogenesis similar to miR‐214 overexpression. Furthermore, ectopic expression of XBP1 enhances endothelial cells proliferation and tube formation, and reverses anti‐angiogenic effect of miR‐214 over expression. All these findings suggest that miR‐214 is an important regulator of angiogenesis in heart in vitro and in vivo, likely via regulating the expression of XBP1, and demonstrate that miR‐214 plays an essential role in the control/inhibition of cardiac angiogenesis. J. Cell. Physiol. 230: 1964–1973, 2015. © 2015 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.
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Affiliation(s)
- Quanlu Duan
- Department Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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Di Y, Zhang D, Hu T, Li D. miR-23 regulate the pathogenesis of patients with coronary artery disease. Int J Clin Exp Med 2015; 8:11759-11769. [PMID: 26380016 PMCID: PMC4565399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 04/23/2015] [Indexed: 06/05/2023]
Abstract
To study whether miR-23 is regulated in coronary artery disease (CAD) patients and what is the possible mechanism of miR-23 in regulating CAD progression. Method Three different cohorts (including 13 AMI patients, 176 angina pectoris patients and 127 control subjects) were enrolled to investigate the expression levels of circulating miR-23 in patients with myocardial ischemia and also the relationship between plasma miR-23 and severity of coronary stenosis. Plasma miR-23 levels of participants were examined by real-time quantitative PCR. We further detected the correlation of miR-23 and VEGF by molecular and animal assays. Result miR-23 was enriched in not only diseased endothelial progenitor cells (EPCs) but also the plasma of CAD patients. Besides, we found out miR-23 was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-23 to the 3'-UTR of VEGF mRNA. Knock down of miR-23 not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Conclusion Circulating miR-23 may be a new biomarker for CAD and as a potential diagnostic tool. And increased miR-23 level may be used to predict the presence and severity of coronary lesions in CAD patients.
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Affiliation(s)
- Yunfeng Di
- Department of Cardiology, Sichuan Mianyang 404 Hospital (The Second Affiliated Hospital of North Sichuan Medical College) Sichuan, China
| | - Dayong Zhang
- Department of Cardiology, Sichuan Mianyang 404 Hospital (The Second Affiliated Hospital of North Sichuan Medical College) Sichuan, China
| | - Teng Hu
- Department of Cardiology, Sichuan Mianyang 404 Hospital (The Second Affiliated Hospital of North Sichuan Medical College) Sichuan, China
| | - Decai Li
- Department of Cardiology, Sichuan Mianyang 404 Hospital (The Second Affiliated Hospital of North Sichuan Medical College) Sichuan, China
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Circulating MicroRNAs: Potential and Emerging Biomarkers for Diagnosis of Cardiovascular and Cerebrovascular Diseases. BIOMED RESEARCH INTERNATIONAL 2015; 2015:730535. [PMID: 26180810 PMCID: PMC4477423 DOI: 10.1155/2015/730535] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 05/11/2015] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) are composed of a group of endogenous and noncoding small RNAs which control expression of complementary target mRNAs. The extended functions of miRNAs enhance the complexity of gene-regulatory processes in cardiovascular and cerebrovascular diseases. Indeed, recent studies have shown that miRNAs are closely related to myocardial infarction, heart failure, atrial fibrillation, cardiomyopathy, hypertension, angiogenesis, coronary artery disease, dyslipidaemia, stroke, and so forth. These findings suggest a new therapeutic pointcut for cardiovascular and cerebrovascular diseases and show the extensive therapeutic potential of miRNA regulation. Moreover, it has been shown that circulating extracellular miRNAs are stable in bodily fluids, which indicates circulating miRNAs as potential and emerging biomarkers for noninvasive diagnosis. This review highlights the most recent findings indicative of circulating miRNAs as potential clinical biomarkers for diagnosis of cardiovascular and cerebrovascular diseases.
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Schulte C, Zeller T. microRNA-based diagnostics and therapy in cardiovascular disease-Summing up the facts. Cardiovasc Diagn Ther 2015; 5:17-36. [PMID: 25774345 DOI: 10.3978/j.issn.2223-3652.2014.12.03] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 12/21/2022]
Abstract
Circulating microRNAs (miRNAs) are discussed as potential disease-specific biomarkers in cardiovascular disease. Their diagnostic value has been examined in numerous studies and animal models with respect to coronary artery disease (CAD) and myocardial infarction (MI) and the prognostic abilities of circulating miRNAs in risk stratification of future disease have been evaluated. Various miRNAs are described to complement protein-based biomarkers or classical risk factors in the diagnosis of CAD or MI and even represent potential new biomarkers in the discrimination of unstable angina pectoris (UAP). Signatures consisting of sets of multiple miRNAs seem to improve the predictive power compared to single miRNAs. Furthermore, the emerging field of miRNA-based therapeutics has reached cardiovascular research. The first promising in vitro results are raising hope for future clinical application. However, methods and material used for RNA isolation, miRNA detection and normalization steps still lack ways of standardization and need to be considered carefully. This article reviews the current knowledge of miRNAs in cardiovascular disease focusing on CAD and MI and will provide an overview regarding the use of circulating miRNAs as biomarkers and potential therapeutic targets in the field of CAD.
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Affiliation(s)
- Christian Schulte
- 1 Department of General and Interventional Cardiology, University Heart Center Hamburg Eppendorf, 20246 Hamburg, Germany ; 2 German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Hamburg, Germany
| | - Tanja Zeller
- 1 Department of General and Interventional Cardiology, University Heart Center Hamburg Eppendorf, 20246 Hamburg, Germany ; 2 German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Hamburg, Germany
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Mediated protective effect of electroacupuncture pretreatment by miR-214 on myocardial ischemia/reperfusion injury. JOURNAL OF GERIATRIC CARDIOLOGY : JGC 2015; 11:303-10. [PMID: 25593579 PMCID: PMC4294147 DOI: 10.11909/j.issn.1671-5411.2014.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/10/2014] [Accepted: 10/17/2014] [Indexed: 12/30/2022]
Abstract
Background Electroacupuncture pretreatment plays a protective role in myocardial ischemia/reperfusion (I/R) injury and microRNAs (miRNAs) could act on various facets of cardiac function. However, the role of miRNAs in the cardioprotection by electroacupuncture pretreatment on myocardial I/R injury remains unknown. The purpose of the study was to examine whether miR-214 was involved in cardioprotection by electroacupuncture. Methods Using rat myocardial I/R model, we examined the role of electroacupuncture pretreatment in myocardial I/R injury and analyzed the changes in the expression of miR-214. In addition, I/R was simulated in vitro by performing oxygen-glucose deprivation (OGD) on H9c2 cell cultures, and the effect of electroacupuncture pretreatment on I/R injury as well as expressional level of miR-214 were examined in vitro. Furthermore, the miR-214 mimic was transfected into OGD-treated H9c2 cells, we analyzed the cell apoptosis, lactate dehydrogenase (LDH) and creatine kinase (CK) activities, intracellular free Ca2+ concentration ([Ca2+]i) as well as the relative protein levels of sodium/calcium exchanger 1(NCX1), BCL2-like 11 (BIM), calmodulin-dependent protein kinase IIδ (CaMKIIδ) and Cyclophilin D (CypD). Results The in vivo results revealed that compared with the I/R group, the electroacupuncture pretreatment group showed significant decreased myocardial infarct size, as well as the increased indices of the cardiac function, including heart rate, mean arterial pressure, left ventricular systolic pressure and maximal rate for left ventricular pressure rising and declining (±dp/dt max). In addition, electroacupuncture pretreatment could inhibit the elevation of LDH and CK activities induced by I/R injury. The quantitative PCR (qPCR) results demonstrated electroacupuncture pretreatment could provide cardioprotection against myocardial I/R injury in rats with miR-214 up-regulation. In the meanwhile, in vitro, electroacupuncture pretreatment protected H9c2 cells from OGD-induced injury. Transfection of miR-214 mimic showed protective effects on OGD-induced injury to H9c2 cells by reducing apoptosis, decreasing LDH and CK activities, rescuing the OGD-induced Ca2+ and down-regulating elevated protein levels of NCX1, BIM, CaMKIIδ and CypD. Conclusions Our findings firstly demonstrated that electroacupuncture pretreatment promotes the expression of miR-214 in myocardial I/R injury and miR-214 contributes to the protective effect of electroacupuncture on myocardial I/R injury.
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28
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MiR-214 regulates the pathogenesis of patients with coronary artery disease by targeting VEGF. Mol Cell Biochem 2015; 402:111-22. [PMID: 25575606 DOI: 10.1007/s11010-014-2319-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 12/23/2014] [Indexed: 12/11/2022]
Abstract
Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. We aimed to investigate the correlation between the levels of circulating miR-214 and the expression of vascular endothelial growth factor (VEGF) in the pathogenesis of coronary heart disease patients to further explore the mechanism involved in the vasculogenesis. Three different cohorts, including 13 acute myocardial infarction patients, 176 angina pectoris patients, and 127 control subjects, were enrolled to investigate the expression levels of circulating miR-214 in patients with myocardial ischemia and also the relationship between plasma miR-214 and severity of coronary stenosis. Plasma miR-214 levels of participants were examined by real-time quantitative PCR. Simultaneously, plasma cardiac troponin I concentrations were measured by ELISA assays. We further detected the correlation of miR-214 and VEGF by molecular and animal assays. MiR-214 was enriched in not only diseased endothelial progenitor cells (EPCs) but also the plasma of coronary artery disease (CAD) patients. Besides, we found out miR-214 was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-214 to the 39-UTR of VEGF mRNA. Knockdown of miR-214 not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but also further promoted blood flow recovery in ischemic limbs of mice. Circulating miR-214 may be a new biomarker for CAD and as a potential diagnostic tool. And increased miR-214 level may be used to predict the presence and severity of coronary lesions in CAD patients.
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29
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Katoh M. Cardio-miRNAs and onco-miRNAs: circulating miRNA-based diagnostics for non-cancerous and cancerous diseases. Front Cell Dev Biol 2014; 2:61. [PMID: 25364765 PMCID: PMC4207049 DOI: 10.3389/fcell.2014.00061] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 09/29/2014] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases and cancers are the leading causes of morbidity and mortality in the world. MicroRNAs (miRNAs) are short non-coding RNAs that primarily repress target mRNAs. Here, miR-24, miR-125b, miR-195, and miR-214 were selected as representative cardio-miRs that are upregulated in human heart failure. To bridge the gap between miRNA studies in cardiology and oncology, the targets and functions of these miRNAs in cardiovascular diseases and cancers will be reviewed. ACVR1B, BCL2, BIM, eNOS, FGFR3, JPH2, MEN1, MYC, p16, and ST7L are miR-24 targets that have been experimentally validated in human cells. ARID3B, BAK1, BCL2, BMPR1B, ERBB2, FGFR2, IL6R, MUC1, SITR7, Smoothened, STAT3, TET2, and TP53 are representative miR-125b targets. ACVR2A, BCL2, CCND1, E2F3, GLUT3, MYB, RAF1, VEGF, WEE1, and WNT7A are representative miR-195 targets. BCL2L2, ß-catenin, BIM, CADM1, EZH2, FGFR1, NRAS, PTEN, TP53, and TWIST1 are representative miR-214 targets. miR-125b is a good cardio-miR that protects cardiomyocytes; miR-195 is a bad cardio-miR that elicits cardiomyopathy and heart failure; miR-24 and miR-214 are bi-functional cardio-miRs. By contrast, miR-24, miR-125b, miR-195, and miR-214 function as oncogenic or tumor suppressor miRNAs in a cancer (sub)type-dependent manner. Circulating miR-24 is elevated in diabetes, breast cancer and lung cancer. Circulating miR-195 is elevated in acute myocardial infarction, breast cancer, prostate cancer and colorectal adenoma. Circulating miR-125b and miR-214 are elevated in some cancers. Cardio-miRs and onco-miRs bear some similarities in functions and circulation profiles. miRNAs regulate WNT, FGF, Hedgehog and other signaling cascades that are involved in orchestration of embryogenesis and homeostasis as well as pathogenesis of human diseases. Because circulating miRNA profiles are modulated by genetic and environmental factors and are dysregulated by genetic and epigenetic alterations in somatic cells, circulating miRNA association studies (CMASs) within several thousands of cases each for common non-cancerous diseases and major cancers are necessary for miRNA-based diagnostics.
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Affiliation(s)
- Masaru Katoh
- Department of Omics Network, National Cancer Center Tokyo, Japan
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Chevillet JR, Lee I, Briggs HA, He Y, Wang K. Issues and prospects of microRNA-based biomarkers in blood and other body fluids. Molecules 2014; 19:6080-105. [PMID: 24830712 PMCID: PMC6271291 DOI: 10.3390/molecules19056080] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 05/07/2014] [Accepted: 05/12/2014] [Indexed: 12/21/2022] Open
Abstract
Cell-free circulating microRNAs (miRNAs) in the blood are good diagnostic biomarker candidates for various physiopathological conditions, including cancer, neurodegeneration, diabetes and other diseases. Since their discovery in 2008 as blood biomarkers, the field has expanded rapidly with a number of important findings. Despite the initial optimistic views of their potential for clinical application, there are currently no circulating miRNA-based diagnostics in use. In this article, we review the status of circulating miRNAs, examine different analytical approaches, and address some of the challenges and opportunities.
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Affiliation(s)
| | - Inyoul Lee
- Institute for Systems Biology, Seattle, WA 98109, USA
| | - Hilary A Briggs
- Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, NY 10065, USA
| | - Yuqing He
- Institute of Medical Systems Biology, Guangdong Medical College, Dongguan, Guangdong 523808, China.
| | - Kai Wang
- Institute for Systems Biology, Seattle, WA 98109, USA.
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Novák J, Bienertová-Vašků J, Kára T, Novák M. MicroRNAs involved in the lipid metabolism and their possible implications for atherosclerosis development and treatment. Mediators Inflamm 2014; 2014:275867. [PMID: 24876669 PMCID: PMC4020222 DOI: 10.1155/2014/275867] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/21/2014] [Accepted: 04/03/2014] [Indexed: 02/07/2023] Open
Abstract
Hyperlipidemia is a well-accepted risk factor in the development of atherosclerosis. MicroRNAs (miRNAs), a novel class of posttranscriptional regulators of gene expression, are involved in a variety of biological and pathological processes, including the regulation of the lipid metabolism and atherosclerosis. As our knowledge of miRNAs expands, a new class of "circulating miRNAs" has recently been described. It includes miRNAs which may be found in various bodily fluids packaged in microvesicles/exosomes, or bound to specific transporting proteins. High-density lipoprotein (HDL) particles have been identified as one such carrier. As this class of miRNAs likely plays a role in intercellular communication, it may also contribute to the atherosclerosis development and progression. This review aims to provide a comprehensive explanation of the roles of distinct miRNAs involved in the regulation of the lipid metabolism. These microRNAs seem to be promising therapeutic agents, as documented in rodents and African green monkeys. The second part of the review focuses on circulating miRNAs and their involvement in the atherosclerosis, especially as their levels have been described as altered in patients with dyslipidemia/hyperlipidemia. Special emphasis is placed on miRNAs transported in a complex with HDL particles and on those which may be considered potential atherosclerosis biomarkers.
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Affiliation(s)
- Jan Novák
- International Clinical Research Center, Department of Cardiovascular Diseases, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A20, 625 00 Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A18, 625 00 Brno, Czech Republic
| | - Julie Bienertová-Vašků
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Building A18, 625 00 Brno, Czech Republic
| | - Tomáš Kára
- International Clinical Research Center, Department of Cardiovascular Diseases, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic
| | - Miroslav Novák
- International Clinical Research Center, Department of Cardiovascular Diseases, St. Anne's University Hospital Brno, Pekarska 53, 656 91, Brno, Czech Republic
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Li J, Xu J, Cheng Y, Wang F, Song Y, Xiao J. Circulating microRNAs as mirrors of acute coronary syndromes: MiRacle or quagMire? J Cell Mol Med 2013; 17:1363-70. [PMID: 24188699 PMCID: PMC4117549 DOI: 10.1111/jcmm.12148] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Accepted: 08/29/2013] [Indexed: 12/15/2022] Open
Abstract
Acute coronary syndrome (ACS), a leading cause of morbidity and mortality worldwide, is among the most serious cardiovascular diseases. Exploring novel approaches, which can complement and improve current strategies for ACS, is continuous. MicroRNAs (miRNAs) are a novel class of small, short non-coding RNA that post-transcriptionally regulate genes. The tissue- or cell-specific distribution features of miRNAs and its merit of stably existing in serum and plasma make them attractive biomarkers for ACS. An early and accurate diagnosis is the pre-requisite to facilitate rapid decision making and treatment and therefore improve outcome in ACS patients. This review highlights and summarizes recent studies using circulating miRNAs as novel biomarkers for ACS including its role in diagnosis, prediction, prognosis and reaction to therapy. In addition, we also discuss the potential function of miRNAs as extracellular communicators in cell-to-cell communication. Large multicentre studies are highly needed to pave the road for using circulating miRNAs as biomarkers for ACS from the bench to the bedside. Considering the advantageous properties and the continuously increasing number of studies, circulating miRNAs definitely have the potential to be reasonable diagnostic tools once their infancy has passed.
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Affiliation(s)
- Jin Li
- Regeneration Lab, School of Life Science, Shanghai University, Shanghai, China; Experimental Center of Life Sciences, Shanghai University, Shanghai, China
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